This invention pertains to a replication deficient adenoviral vector comprising a nucleic acid sequence coding for tumor necrosis factor (TNF), as well as a method of constructing and using such vector.
Tumor necrosis factor (TNF), especially TNF-xcex1, is well-known for its anti-tumor effects and ability to act synergistically with radiation therapy. For example, certain replication deficient adenoviral vectors comprising the TNF-xcex1 gene have been used in conjunction with radiation therapy to treat tumors in animals with some success (e.g., Hallahan et al., Nat. Med., 1, 786-91 (1995)). The use of TNF as an anti-cancer/anti-tumor agent, however, has been limited by its severe systemic effects.
There remains a need for replication deficient TNF adenoviral vectors that have greater flexibility in their construction and use, and can provide greater success in the treatment of a tumor or cancer. The present invention provides such a vector, as well as a method of constructing such vector, and a therapeutic method involving the use of such vector.
The present invention provides an adenoviral vector comprising (a) an adenoviral genome deficient in the early growth-4 (E4) region of the adenoviral genome, (b) a nucleic acid sequence coding for TNF, and (c) a radiation inducible promoter operably linked to the nucleic acid sequence coding for TNF. This invention also provides an adenoviral vector comprising (a) an adenoviral genome deficient in the E4 region of the adenoviral genome, (b) a nucleic acid sequence coding for TNF, and (c) a spacer element of at least 15 base pairs in the E4 region of the adenoviral genome.
A method of producing an adenoviral vector also is provided by the present invention comprising (a) providing an adenoviral genome that is deficient in the E4 region of the adenoviral genome, (b) inserting a nucleic acid sequence coding for TNF into the adenoviral genome, and (c) inserting a radiation-inducible promoter into the adenoviral genome such that it is operably linked to the nucleic acid sequence coding for TNF. This invention further provides a method of treating a tumor or cancer in a host comprising administering an anti-cancer or anti-tumor effective amount of the adenoviral vector of the present invention to a host in need thereof.
The present invention may best be understood with reference to the accompanying drawings and in the following detailed description of the preferred embodiments.